Guidance for Industry
`
`Nasal Spray and Inhalation Solution, Suspension,
`and Spray Drug Products — Chemistry,
`Manufacturing, and Controls Documentation
`
``
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`
`July 2002
`
`CMC
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`Guidance for Industry
`
`Nasal Spray and Inhalation Solution,
`Suspension, and Spray Drug Products —
`Chemistry, Manufacturing, and Controls
`Documentation
`
`Additional copies are available from:
`
`Office of Training and Communications
`Division of Drug Information, HFD-240
`Center for Drug Evaluation and Research
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, MD 20857
`(Tel) 301-827-4573
`http://www.fda.gov/cder/guidance/index.htm
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`
`July 2002
`
`CMC
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`TABLE OF CONTENTS
`INTRODUCTION................................................................................................................. 1
`I.
`...................................................................................................................
`II. BACKGROUND
`2
`A. Nasal Sprays .........................................................................................................................2
`B.
`Inhalation Solutions and Suspensions ...................................................................................3
`C.
`Inhalation Sprays..................................................................................................................3
`III.
`DRUG PRODUCT............................................................................................................ 5
`A.
`Formulation Components .....................................................................................................5
`B.
`Formulation Composition.....................................................................................................5
`...................................................................
`C.
`Specifications for the Formulation Components
`5
`........................................................................................................................
`D. Manufacturer
`9
`E. Method of Manufacture and Packaging ................................................................................9
`F.
`Specifications for the Drug Product ....................................................................................10
`G. Container Closure Systems .................................................................................................22
`H. Drug Product Stability........................................................................................................27
`IV. DRUG PRODUCT CHARACTERIZATION STUDIES................................................ 32
`A.
`Priming and Repriming in Various Orientations ................................................................33
`B. Effect of Resting Time.........................................................................................................33
`C. Temperature Cycling ..........................................................................................................33
`D.
`In Vitro Dose Proportionality .............................................................................................34
`E. Cleaning Instructions..........................................................................................................34
`F. Device Robustness
`34
`...............................................................................................................
`G. Effect of Dosing Orientation ...............................................................................................34
`H. Effect of Varying Flow Rates ..............................................................................................35
`..........................
`I.
`Profiling of Sprays Near Container Exhaustion (Tail Off Characteristics)
`35
`J.
`Effect of Storage on the Particle Size Distribution ..............................................................35
`K. Plume Geometry .................................................................................................................36
`L.
`Preservative Effectiveness and Sterility Maintenance .........................................................36
`M. Characterization of Nebulizer Specified in the Labeling.....................................................36
`......................................................................................................................
`N.
`Photostability
`36
`O.
`Stability of Primary (Unprotected) Package........................................................................37
`V. LABELING CONSIDERATIONS
`....................................................................................
`37
`A. Nasal and Inhalation Spray Drug Products
`37
`.........................................................................
`B.
`Inhalation Solutions and Suspensions .................................................................................40
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`GLOSSARY OF TERMS ........................................................................................................... 43
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`GUIDANCE FOR INDUSTRY1
`
`Nasal Spray and Inhalation Solution, Suspension, and Spray Drug
`Products — Chemistry, Manufacturing, and Controls Documentation
`
`This guidance represents the Food and Drug Administration's (FDA's) current thinking on this
`topic. It does not create or confer any rights for or on any person and does not operate to bind
`FDA or the public. An alternative approach may be used if such approach satisfies the
`requirements of the applicable statutes and regulations.
`
`I.
`
`INTRODUCTION
`
`This document provides guidance for industry on the chemistry, manufacturing, and
`controls (CMC) documentation that should be submitted in new drug applications
`(NDAs) and abbreviated new drug applications (ANDAs) for nasal spray and inhalation
`solution, suspension, and spray drug products intended for local and/or systemic effect.
`This guidance covers CMC information recommended for inclusion in the application
`regarding the drug product components, manufacturing process, and associated controls
`for each of these areas, but does not address the manufacture of drug substances. The
`guidance also provides recommendations on labeling. This guidance does not address
`propellant-based inhalation and nasal aerosols (also known as oral and nasal metered-
`dose inhalers, MDIs), inhalation powders (also known as dry powder inhalers, DPIs), and
`nasal powders.2
`
`This guidance sets forth information that should be provided to ensure continuing quality
`and performance characteristics for these drug products. The guidance does not impose
`mandatory requirements but does suggest approaches that are appropriate for submitting
`CMC-related regulatory information. The guidance provides recommendations for drug
`
`1 This guidance has been prepared by the Inhalation Drug Products Working Group of the
`Chemistry, Manufacturing, and Controls Coordinating Committee (CMCCC) in the Center for Drug
`Evaluation and Research (CDER) at the FDA.
`
`2 In November 1998 (63 FR 64270), the Agency made available a draft guidance document on
`Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products
` Chemistry, Manufacturing,
`and Controls Documentation. When finalized, this guidance will provide CMC recommendations for
`MDIs and DPIs.
`
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`products that are used to treat a variety of diseases and patient populations. Therefore,
`CMC recommendations may vary depending on the specific drug product and stage of
`development. For example, the recommendations in this guidance should be considered
`during the investigational stages and phased in by the initiation of critical clinical studies
`(phase 2 and phase 3 studies) to provide supporting documentation for an NDA.
`Applicants are encouraged to discuss significant departures from the approaches outlined
`in this guidance (including decisions to provide less CMC documentation than
`recommended) with the appropriate Agency review division before implementation to
`avoid expending resources on development avenues that may later be deemed
`inappropriate.
`
`Reference to information in Drug Master Files (DMFs) for particular portions of the
`CMC section of the application is appropriate if the DMF holder provides written
`authorization that includes specific reference (e.g., submission date, page number, item
`name and unique identifier) to the pertinent and up-to-date information (21 CFR
`314.420(d)). Refer to FDA•s Guideline for Drug Master Files (September 1989) for
`more information about DMFs.
`
`II.
`
`BACKGROUND
`
`A.
`
`Nasal Sprays
`
`Nasal spray drug products contain therapeutically active ingredients (drug
`substances) dissolved or suspended in solutions or mixtures of excipients (e.g.,
`preservatives, viscosity modifiers, emulsifiers, buffering agents) in
`nonpressurized dispensers that deliver a spray containing a metered dose of the
`active ingredient. The dose can be metered by the spray pump or could have been
`premetered during manufacture. A nasal spray unit can be designed for unit
`dosing or can discharge up to several hundred metered sprays of formulation
`containing the drug substance. Nasal sprays are applied to the nasal cavity for
`local and/or systemic effects.
`
`Although similar in many features to other drug products, some aspects of nasal
`sprays may be unique (e.g., formulation, container closure system, manufacturing,
`stability, controls of critical steps, intermediates, and drug product). These
`aspects should be considered carefully during the development program because
`changes can affect the ability of the product to deliver reproducible doses to
`patients throughout the product•s shelf life. Some of the unique features of nasal
`sprays are listed below:
`
`•
`
`Metering and spray producing (e.g., orifice, nozzle, jet) pump mechanisms
`and components are used for reproducible delivery of drug formulation,
`and these can be constructed of many parts of different design that are
`precisely controlled in terms of dimensions and composition.
`
`2
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`•
`
`•
`
`•
`
`Energy is required for dispersion of the formulation as a spray. This is
`typically accomplished by forcing the formulation through the nasal
`actuator and its orifice.
`
`The formulation and the container closure system (container, closure,
`pump, and any protective packaging) collectively constitute the drug
`product. The design of the container closure system affects the dosing
`performance of the drug product.
`
`The concept of classical bioequivalence and bioavailability may not be
`applicable for all nasal sprays, depending on the intended site of action.
`The doses administered are typically so small that blood or serum
`concentrations are generally undetectable by routine analytical procedures.
`Additional information will be provided in a future guidance for industry
`on Bioavailability and Bioequivalence Studies for Nasal Aerosols and
`Nasal Sprays for Local Action.3
`
`B.
`
`Inhalation Solutions and Suspensions
`
`Inhalation solution and suspension drug products are typically aqueous-based
`formulations that contain therapeutically active ingredients and can also contain
`additional excipients. Aqueous-based oral inhalation solutions and suspension
`must be sterile (21 CFR 200.51). Inhalation solutions and suspensions are
`intended for delivery to the lungs by oral inhalation for local and/or systemic
`effects and are to be used with a specified nebulizer. Unit-dose presentation is
`recommended for these drug products to prevent microbial contamination during
`use. The container closure system for these drug products consists of the
`container and closure, and can include protective packaging such as foil
`overwrap. Recommendations on overwrapping of inhalation drug products
`packaged in semipermeable container closure systems are provided in section
`III.G.5.
`
`C.
`
`Inhalation Sprays
`
`An inhalation spray drug product consists of the formulation and the container
`closure system. The formulations are typically aqueous based and, by definition,
`do not contain any propellant. Aqueous-based oral inhalation sprays must be
`sterile (21 CFR 200.51). Inhalation sprays are intended for delivery to the lungs
`by oral inhalation for local and/or systemic effects. The products contain
`therapeutically active ingredients and can also contain additional excipients. The
`formulation can be in unit-dose or multidose presentations. The use of
`preservatives or stablilizing agents in inhalation spray formulations is
`
`3A notice of availability for the June 1999 draft guidance Bioavailability and Bioequivalence
`Studies for Nasal Aerosols and Nasal Sprays for Local Action published in the Federal Register on June 24,
`1999 (64 FR 33869).
`
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`discouraged. If these excipients are included in a formulation, their use should be
`justified by assessment in a clinical setting to ensure the safety and tolerability of
`the drug product. The dose is delivered by the integral pump components of the
`container closure system to the lungs by oral inhalation for local and/or systemic
`effects. The container closure system of these drug products consists of the
`container, closure, and pump, and can also include protective packaging.
`
`Current container closure system designs for inhalation spray drug products
`include both premetered and device-metered presentations using mechanical or
`power assistance and/or energy from patient inspiration for production of the
`spray plume. Premetered presentations contain previously measured doses or a
`dose fraction in some type of units (e.g., single or multiple blisters or other
`cavities) that are subsequently inserted into the device during manufacture or by
`the patient before use. Typical device-metered units have a reservoir containing
`formulation sufficient for multiple doses that are delivered as metered sprays by
`the device itself when activated by the patient.
`
`Inhalation spray and nasal spray drug products have many similarities. Therefore,
`many of the unique features listed in section II.A for nasal sprays are also
`characteristic of inhalation spray drug products. Moreover, the potential wide
`array of inhalation spray drug product designs with unique characteristics will
`present a variety of development challenges. Regardless of the design, the most
`crucial attributes are the reproducibility of the dose, the spray plume, and the
`particle/droplet4 size distribution, since these parameters can affect the delivery of
`the drug substance to the intended biological target. Maintaining the
`reproducibility of these parameters through the expiration dating period and
`ensuring the sterility of the content and the functionality of the device (e.g., spray
`mechanism, electronic features, sensors) through its lifetime under patient-use
`conditions will probably present the most formidable challenges. Therefore,
`changes in components of the drug product or changes in the manufacturer or
`manufacturing process that can affect these parameters should be carefully
`evaluated for their effect on the safety, clinical effectiveness and stability of the
`product. If such changes are made subsequent to the preparation of the batches
`used in critical clinical, bioequivalence, or primary stability studies, adequate
`supportive comparative data should be provided to demonstrate equivalency in
`terms of safety, clinical effectiveness, and stability of the product.
`
`The remaining portion of this guidance will focus on specific chemistry,
`manufacturing, and controls information recommended for inclusion in the drug
`product section of applications for nasal spray and inhalation solution, suspension,
`and spray drug products.
`
`4 The term particle/droplet refers to a combination of droplets and particles or droplets alone,
`depending on the formulation and conditions of measurement.
`
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`III.
`
`DRUG PRODUCT
`
`A.
`
`Formulation Components
`
`A list of all components (i.e., ingredients) used in the manufacture of the drug
`product formulation, regardless of whether they undergo chemical change or are
`removed during manufacture, should be included in the application. Each
`component should be identified by its established name, if any, and by its
`complete chemical name, using structural formulas when warranted for specific
`identification. If any proprietary preparations or other mixtures are used as
`components, their identity should be fully described including a complete
`statement of their composition and other information that will properly identify
`the material.
`
`B.
`
`Formulation Composition
`
`The application should include a statement of the quantitative composition of the
`unit formula of the drug product, specifying the name and amount of each active
`ingredient and excipient contained in a stated quantity of the formulation. For
`components in the final formulation, the amounts should be expressed in
`concentration (i.e., amount per unit volume or weight), as well as amount per
`container and per spray, where applicable. The target container net content
`should also be indicated. Similarly, a production batch formula representative of
`the one to be employed in the manufacture of the drug product should be
`included. Any calculated overage for an ingredient should be designated as such
`and the percentage shown. The overage should be scientifically justified and
`documented in both the unit formula and batch formula. For these products,
`overages can be included only for justified reproducible manufacturing losses
`and/or for an ANDA product to match the overage present in the Reference Listed
`Drug. Any intended change in the formulation of the commercial product from
`that used in the submitted batches (e.g., critical clinical, biobatch, primary
`stability, production) should be clearly indicated by providing the composition of
`each formulation.
`
`The composition of suspension formulations may be crucial in defining the
`physical stability and the performance characteristics of the drug product. The
`density and suspension properties of the solid materials of the formulation and the
`potential for agglomeration should be considered. Moreover, interaction of the
`suspended drug substance with the various internal container closure system
`components can also contribute to a nonhomogeneous distribution of drug
`substance. The above mentioned phenomena, which may be exacerbated with
`time, can contribute to inconsistent particle size distribution and medication dose
`delivery. See also the discussions in sections III.F.1.c and III.F.2.c.
`
`C.
`
`Specifications for the Formulation Components
`
`5
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`1.
`
`Active Ingredients
`
`Information regarding the comprehensive characterization of the physical and
`chemical properties of the drug substance should be included in the application.
`Important properties of the drug substance used in suspension formulations can
`include, but are not necessarily limited to, density, particle size distribution,
`particle morphology, solvates and hydrates, polymorphs, amorphous forms,
`solubility profile, moisture and/or residual solvent content, microbial quality,
`dissociation constants (pKa), and specific rotation.
`
`Appropriate acceptance criteria and tests for routine control (i.e., release, stability,
`and retest) should be instituted for those drug substance parameters considered
`key to ensuring reproducibility of the physicochemical properties of the drug
`substance. Specification parameters can include, as applicable, color, appearance
`(visual and microscopic), specific identification, moisture, residue on ignition,
`specific rotation, assay, impurities, microbial limits (U.S. Pharmacopeia (USP)
`<61>)5, melting range, particle size distribution, crystalline forms, amorphous
`content, residual solvents, and heavy metals. Some of these parameters may not
`be pertinent for drug substances used in solution formulations.
`
`The purity of the drug substance and its impurity profile should be characterized
`and controlled with appropriate specifications. Important impurity-related
`parameters can include organic volatile impurities and/or residual solvents,
`organic impurities (synthesis-related and degradation products), and inorganic
`impurities (e.g., heavy metals, reagents, catalysts). Any impurity found in the
`drug substance at a concentration of 0.10 percent or 1.0 milligram (mg) per day
`intake (whichever is lower), relative to the parent drug substance, should be
`identified. Moreover, the drug substance impurities should be appropriately
`qualified. Justification of acceptance criteria for the drug substance impurities
`should be based on toxicological considerations and levels of impurities found in
`the submitted batches (e.g., critical clinical, biobatch, primary stability,
`production). For guidance on toxicological qualification, the applicant is
`encouraged to refer to the following guidance documents: (1) ICH Q3A
`Impurities in New Drug Substances (January 1996),6 (2) NDAs: Impurities in
`Drug Substances (February 2000), and (3) ANDAs: Impurities in Drug Substances
`(November 1999). The applicant can also contact the responsible review division
`for guidance on toxicological qualification.
`
`For suspension formulations, the specification for drug substance should include
`controls for particle size distribution and physical properties (e.g., shape, crystal
`
`5 Sample size for microbial limits testing should be 10 grams unless otherwise justified.
`
`6 The guidance, Q3A Impurities in New Drug Substances, will be superseded by FDA’s guidance
`for industry, Q3A(R) Impurities in New Drug Substances, once it is issued in final form. We update
`guidances periodically. To make sure you have the most recent version of a guidance, check the CDER
`guidance page at http://www.fda.gov/cder/guidance/index.htm.
`
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`habit, morphology, surface texture) of the drug substance, parameters that are
`often critical for reproducible drug product performance. If laser diffraction
`methodology is used for testing the particle size distribution, it is crucial that test
`procedure instrumental parameters (e.g., apparatus and accessories, calculation
`theory, correction principles, software version, sample placement, laser trigger
`condition, measurement range, beam width) be defined accurately and with
`sufficient detail for Agency laboratories to validate the adequacy of the
`methodology. In addition, the potential effect of micronization processes on the
`levels of amorphous content and foreign particulates in the drug substance should
`be considered.
`
`In general, acceptance criteria for all parameters defining the physicochemical
`properties should be based on historical data, thereby providing continuity of
`quality and reproducible performance of future batches of the drug substance.
`For additional information on various aspects of drug substance chemistry,
`manufacturing, and controls documentation, see the FDA Guideline for
`Submitting Supporting Documentation in Drug Applications for the Manufacture
`of Drug Substances (February 1987).
`
`2.
`
`Excipients
`
`Because of the route of administration and the sensitive nature of various patient
`populations using oral inhalation (solution, suspension, spray) drug products,
`more thorough characterization with additional comprehensive controls (e.g.,
`strength, quality, purity), as compared to drug products for other routes of
`administration, should be considered for excipients used in these drug products.
`Moreover, for nasal and inhalation suspension formulations, additional controls
`should be applied to critical excipients to ensure safety and effectiveness of the
`drug product. Critical excipients for suspension formulations (e.g.,
`microcrystalline cellulose for nasal sprays) are those that can affect the
`suspension and/or particle characteristics and, therefore, the quality, stability, or
`performance of the drug product. The suitability of the physicochemical
`properties of these critical excipients should be thoroughly investigated and
`documented.
`
`Unless otherwise indicated, the comments below regarding excipients pertain to
`nasal spray and inhalation solution, suspension, and spray drug products.
`
`The source of each excipient should be assessed, and the material supplied should
`meet appropriate acceptance criteria that are based on test results from a minimum
`of one batch used to prepare the submitted batches of drug product (e.g., critical
`clinical, biobatch, primary stability, production). However, for critical excipients
`of suspension formulations, the sources should be identified and test results from
`multiple batches should be provided. Likewise, when the supplier of an excipient
`is changed prior to submission of the application, the new supplier•s ability to
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`provide material of comparative quality should be assessed and supporting data
`should be provided.
`
`For noncompendial excipients, appropriate authorization to a DMF that provides
`information on the noncompendial excipient or an equivalent package of
`information prepared by the excipient manufacturer should be provided in the
`application. The information should include analytical procedures, acceptance
`criteria, and a brief description of the manufacture and controls.
`
`When a USP or National Formulary (NF) monograph material is used, the
`associated specifications may not always provide adequate assurance with regard
`to the assay, quality, or purity of the material or its performance in the drug
`product. In these cases, monograph specifications should be supplemented with
`appropriate controls (e.g., particle size distribution, crystal forms, amorphous
`content, foreign particulates) to ensure batch-to-batch reproducibility of these
`components. This can be particularly relevant for compendial excipients that
`have an impact on the purity of inhalation drug products or performance
`properties (e.g., droplet and particle size distribution, spray content uniformity) of
`suspension drug products. The additional test procedures should be included, and
`the acceptance criteria should reflect the data for the excipients used in the
`submitted batches (e.g., critical clinical, biobatch, primary stability, production).
`Acceptance criteria for physicochemical parameters of a qualified polymeric
`excipient (e.g., molecular weight distribution, viscosity) that are wider than what
`is reflective of the data on the submitted batches can be justified by demonstrating
`that the proposed ranges of the excipient attributes do not adversely affect the
`quality of the drug product. Justification should be based on adequate release and
`stability data that is specific to the drug product prepared with the excipient
`attributes near the limits of the allowable range.
`
`The suitability of the toxicological properties of the excipients for these drug
`products should be thoroughly investigated and documented. Toxicological
`qualification of these excipients may be appropriate under various circumstances,
`including (1) increased concentration of an excipient above that previously used
`in inhalation and nasal drug products, (2) excipients that have been used
`previously in humans but not by the inhalation or nasal route, and (3) novel
`excipients not previously used in humans in the United States. The extent of
`toxicological investigation to qualify the use of an excipient under such
`circumstances will vary, and the applicant is encouraged to contact the
`responsible review division to discuss an appropriate strategy for toxicological
`qualification.
`
`If excipients are accepted based on certificates of analysis from the manufacturers
`with the applicant performing a specific identification test upon receipt, the
`applicant should also develop validated procedures, have access to all of the
`manufacturer•s analytical and other test procedures, or use contract laboratories to
`allow them to establish the reliability of the test results at appropriate intervals, as
`required under 21 CFR 211.84. The applicant should confirm the supplier•s
`
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`results by (1) testing an adequate number of batches of each excipient used in
`preparing the submitted drug product batches (e.g., critical clinical, primary
`stability, biobatch, production batches) and (2) providing a commitment to test a
`predetermined number of batches of each excipient used in preparing
`postapproval drug product batches.
`
`D.
`
`Manufacturers
`
`The name, street address, and, if available, registration number7 of each facility
`involved in the manufacture of the drug substance should be listed along with a
`statement of each manufacturer's specific operations and responsibilities. The
`same information should be provided for each facility involved in the
`manufacturing, processing, packaging, controls, stability testing, or labeling of the
`drug product, including all contractors (e.g., test laboratories, packagers, labelers).
`For sterile drug products, building numbers, filling rooms, and filling lines should
`also be identified. Manufacturers of critical and novel excipients should be
`identified by name and address.
`
`E.
`
`Method of Manufacture and Packaging
`
`A detailed description of the manufacturing, processing, and packaging
`procedures for the drug product should be included.
`
`All aqueous-based oral inhalation drug products must be manufactured as sterile
`products (21 CFR 200.51), and their sterility should be ensured through the
`expiration dating period.
`
`If micronization is used for the drug substance and/or excipients, the process
`should be fully validated and the equipment, operating conditions, and process
`controls should be described in detail. For example, the description of the
`controls for a milling operation could include the rate of feed, air pressure, air
`flow rate, particle size being fed, number of times a lot is micronized, re-use of
`carryovers from previous micronized lots. Potential contamination of the material
`during the micronization process should be controlled with appropriate tests and
`acceptance criteria. See the discussion of testing attributes specific for
`micronized material (e.g., particle size distribution, crystal forms, amorphous
`content, foreign particulates) discussed in section III.C.1.
`
`A copy of the actual (executed) batch record, including process controls, and
`controls for critical steps and intermediates should be submitted, as appropriate,
`for representative batches (e.g., critical clinical, biobatch, primary stability). A
`schematic diagram of the proposed production process, a list of process controls,
`and a master batch production and controls record should be submitted. A brief
`
`7 Information on when registration is required and how to register is available in 21 CFR 207.
`
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`description of the packaging operations and associated process controls for these
`operations should also be included.
`
`The manufacturing directions should include control procedures and specific
`information on processing variables (such as times, mixing speeds, and
`temperatures) to decrease controllable process variability and increase consistency
`in the quality of the drug product. Any formulation overfill per container to
`achieve a labeled deliverable volume should be appropriately justified.
`
`A description of the controls for critical steps and intermediates, a description of
`the associated analytical procedures, and appropriate data to support the
`acceptance criteria should be provided. These controls should be performed at
`specified production steps and can include, for example, assay, osmolality, pH,
`viscosity, consistency of filling, and quality of sealing.
`
`If protective packaging (such as a foil overwrap) is used for the drug product, the
`application should include a brief descript